DESCRIPTION: This is a renewal application that will use neurophysiologic methods of electrophysiologic recording to test the general hypothesis that signaling interactions occur between the immune system and nervous system of the gastrointestinal tract. The current proposal focuses mainly on the mast cell component of the immunologic cell population and tests the hypothesis that mast cells function to signal the presence of specific allergens to the enteric nervous system. The enteric nervous system responds in a specific way by calling-up a specialized behavioral program stored in its microcircuits which leads to a stereotypic pattern of intestinal behavior of copious secretion of water, mucous and electrolytes in coordination with a powerful propulsive motility pattern. This response pattern functions to expel allergens from the lumen with accompanying symptoms of diarrhea and abdominal pain. Aim 1 will identify the actions on enteric neurons of histamine released by intestinal mast cells during allergen-induced degranulation in the myenteric and submucous plexuses of the small and large intestine and the myenteric plexus of the stomach. Aim 2 will determine the morphological and immunohistochemical types of enteric neurons on which specific effects of allergen-induced release of histamine occur. Aims 3 and 4 will determine how inflammatory cytokines affect morphologically identified enteric neurons using approaches similar to those in aims 1 and 2. Aim 5 is to identify how enteric neural networks interact and respond to signals from immune cells. Aim 6 will determine how the enterotoxin of Clostridium difficile acts on the intestinal nervous system to evoke neurogenic inflammation. The overall goal of the study is to understand better the neurophysiology underlying gastrointestinal immuno-neural communication and its involvement in the symptomatology of diarrhea, abdominal pain and intestinal inflammation.